The cellular cytoskeleton consists of three primary structural elements—actin microfilaments, intermediate filaments, and microtubules (for detailed discussion, see Chapter 38, "Role of the Endothelial Cell Cytoskeleton in Microvascular Function"). The actin cytoskeleton is a dynamic structure that undergoes rearrangement under the control of various actin binding, capping, nucleating, and severing proteins that are intimately involved in regulating the cell shape, motility, and contractile status of cells. Early studies revealed the primary role of actin filaments in EC permeability as demonstrated by the observations that cytochalasin D, which disrupts the actin cytoskeleton, increases EC permeability, while phallacidin, an actin stabilizer, prevents barrier disruption by various agonists. Providing a structural framework to the cell, the actin microfilament system is focally linked to multiple membrane adhesive proteins that connect it to cell-cell (adherens junctions, tight junctions) and cell-matrix (focal adhesion) junctions that anchor the endothelium. In addition, actin filaments, through interaction with myosin, are critical to EC tensile force generation necessary for cell shape changes and barrier regulation (as discussed in detail later).
The functional roles of microtubule and intermediate filament cytoskeletal components in EC barrier regulation are less well defined. Microtubules, polymers of a and b-tubulin forming a lattice network of rigid hollow rods spanning the cell that undergo frequent assembly and disassembly, interact functionally with actin filaments during dynamic cellular processes. Microtubule disruption with agents such as nocodazole or vinblastine induces rapid rearrangement of actin filaments and focal adhesions, cellular contraction, and increased permeability across EC mono-layers, while microtubule stabilization with paclitaxel attenuates these effects. These results suggest that actin microfilament-microtubule crosstalk plays an important, but still poorly defined, role in EC barrier regulation.
Although the third major element involved in EC cytoskeletal structure, intermediate filaments (IFs), exhibit greater diversity than the highly conserved components of actin microfilaments or microtubules, IF proteins share a common dimer structure containing two parallel a-helices that associate with IF-binding proteins that in turn connect to the nuclear envelope, peripheral cell junctions, and other cytoskeletal components. Vimentin, the primary IF protein found in EC and other cells of mesenchymal origin, does not appear to have an essential function in EC barrier regulation. Fibroblasts derived from vimentin knockout mice have normal actin and microtubule architecture, while the animals themselves develop normally without any obvious pheno-typic abnormalities, suggesting that functional roles for IF in EC barrier function are subject to compensation by biologic redundancy.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.